BCL-2 is the founding member of a family of anti- and pro-apoptotic proteins that form an interaction network to regulate the critical homeostatic balance between cellular life and death1,2. The original discovery of BCL-2 at the t(14;18) chromosomal breakpoint of follicular lymphoma expanded the paradigm for cancer pathogenesis to include the inability to undergo programmed cell death3-5. The pathologic overexpression of anti-apoptotic BCL-2 and its functional homologues BCL-XL, BCL-w, MCL-1, and BFL-1/A1 has emerged as a causative mechanism for the development, maintenance, and chemoresistance of many human cancers6,7.
The anti-apoptotic proteins contain a surface groove that can bind and sequester—with differential potency and specificity—the BH3 death domains of pro-apoptotic members8,9. BH3-only pro-apoptotics such as BID and BIM contain a single BH3 domain and function as afferent sensors of cellular stress, delivering their death message to the “multidomain” anti- and pro-apoptotic members, which regulate the cellular life-death decision at the level of the mitochondrion10. When activated directly by BH3-only interaction and/or indirectly by BH3-only-mediated competitive displacement from anti-apoptotics, the multidomain pro-apoptotic proteins BAX and BAK undergo a monomer-to-oligomer transformation that results in outer mitochondrial membrane poration and release of apoptogenic factors11. Whereas cancer cells deploy the anti-apoptotic proteins to silence this pro-apoptotic pathway, pharmacologic antagonists of anti-apoptotic proteins hold promise to restore the death pathway in cancer. Thus, a series of small molecule screens and structure-based methodologies were initially applied to target BCL-2, yielding an eclectic array of small molecules and peptides with various degrees of biochemical, cellular, and in vivo activity12-21. ABT-263 is an orally bioavailable and selective BCL-2/BCL-XL inhibitor, which is advancing through the clinical trials process, manifesting both safety and preliminary efficacy in BCL-2-dependent cancers22-25.
Broad experimentation with the ABT-263 molecule and its progenitor ABT-737 revealed that expression of anti-apoptotic proteins lying outside their binding spectra caused resistance26-29, compelling the development of alternative or complementary agents that would either harbor broader anti-apoptotic targeting capacity or inherent selectivity for anti-apoptotics like MCL-1 and BFL-1/A1 that evade ABT-263/737 antagonism. The small molecule obatoclax15 and the peptidic Stabilized Alpha-Helix of BCL-2 domains (SAHBs) modeled after the BID and BIM BH3 domains30-32 are examples of novel agents that more broadly target the BCL-2 family anti-apoptotic proteins.
WO 2011/094708 discloses small molecules that modulate MCL-1 and/or BFL-1/A1 and methods of using the same, as a single agent or in combination with other drugs, for modulating cell death, cell division, cell differentiation, and treating disorders, such as hyperproliferative disorders.